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  • br Therapeutic approaches exploiting Cx function

    2022-08-18


    Therapeutic approaches exploiting Cx43 function Due to their potential role in cancer metastasis, attempts have been made to alter connexin function to inhibit cancer growth. Therapeutic approaches include Cx43 peptide mimetics, Cx43 inhibitors, chemical agents capable of enhancing Cx43 function, and nanocarriers surface-decorated with Cx43-targeting ligands (Table 2).
    Conclusion
    Conflicts of interest
    Acknowledgements We would like to acknowledge funding by the National Science Foundation (DMR 1751611).
    Introduction Epilepsy, a widespread neurological disorder that has been documented for thousands of years [1], is characterized by sudden, repetitive over-discharge of the LY83583 neurons in the central nervous system (CNS) [2]. Nowadays, it is estimated that nearly 22 million people suffer from epileptic seizures around the world [3,4]. Several syndromes including cognitive decline and depression [[5], [6], [7]], have a detrimental effect on the life quality of patients. According to the previous studies, approximately 6 percent to 52.6 percent of epileptic patients suffered from depression [[8], [9], [10], [11], [12]]. So far, three major medications including surgery, drug therapy and dietary supplementations are employed to ameliorate epileptic seizures, among which pharmacotherapy remains the dominant one [13,14]. In spite of the great progress in the development of new anti-epileptic drugs, there are still about 30% to 40% of patients that are not sensitive to the current drugs [13,[15], [16], [17]]. As early as 2014, it was reported that nearly 100 patients with epilepsy were not well treated with traditional anti-epileptic drugs including valproic acid, levetiracetam, carbamazepine, lamotrigine, topiramate and gabapentin in 218 patients [18]. In addition, several adverse effects such as hepatic toxicity [19], cognitive deficits [20,21] and skin epidermal necrosis (mainly Stevens-Johnson syndrome) [22] often appear after treatment with these antiepileptic drugs [[23], [24], [25]]. Therefore, it is of desperate need to probe the etiology of epileptogenesis and develop the novel drugs for suppressing epilepsy and/or decreasing adverse effects following epileptogenesis.
    Cell communication serves as a great contributor of epileptogenesis The occurrence of epilepsy can be influenced by a variety of factors, such as cell communication, oxidative stress [[26], [27], [28]] and others [29]. There is a general acceptance supporting that epilepsy is triggered by the altered cell communication. Sanae Hasegawa et al. reported that the neuronal communication was remarkably increased in the CA1 region of mice hippocampus following kainic acid-induced neurotoxicity [30]. In general, cell communication contains chemical transmission (indirect communications) and electrical synapses (direct communications). Traditionally, chemical transmission contributes to the generation of epilepsy. It was previously assumed that an imbalance between glutamate-mediated excitatory neurotransmission and γ-aminobutyric acid (GABA)-associated synaptic inhibition resulted in epileptogenesis [[31], [32], [33], [34]]. Substantial investigations depicted that excessive generation of glutamate triggered neuronal hyperexcitability in epileptic patients [[35], [36], [37], [38]]. In addition, it was also found that the level of extracellular glutamate was increased in the focal pilocarpine model of limbic seizures [36]. With further research on the pathogenesis of epilepsy, there is more and more studies illustrating that direct cell-to-cell communication including gap junction (GJ) and mitochondrial transfer [[39], [40], [41]] also serve as a critical contributor of epileptogenesis [42]. It was previously reported that neuronal GJs could modulate the large-scale simultaneous firing of neurons during seizures [43], implying that enhanced GJ is likely to be a basic mechanism in the occurrence of seizures [44,45]. Furthermore, increased electrotonic coupling was reported to facilitate the synchronization of neuronal firing and human primary astrocytes isolated from patients with intractable epilepsy showed increased gap junctional coupling [46]. Besides, in the pilocarpine-induced epileptic model, the expression of connexin36 (Cx36, a common molecule of gap junction) was significantly reduced at 1 h, 4 h and 1 week after status epilepticus, which implied that Cx36 was negatively correlated with the onset of epileptogenesis in the early stage [47]. Similarly, Cx36 knockout was also found to decrease the threshold of pentylenetetrazol (PTZ)-induced seizures in mice [43]. These findings implicate that the GJ-associated molecule Cx36 may serve as a novel target for the treatment of epilepsy.